Iron is an essential nutrient that is regulated by several complex pathways within the body. Dysregulation of iron metabolism leads to common diseases such as hemochromatosis and anemia which affect several hundred million people worldwide. In the past 5 years, our understandings of the basic signaling mechanisms which regulate systemic iron homeostasis have begun to be illuminated. The master regulator of overall iron balance is hepcidin, a key hormone secreted by the liver in response to several stimuli including systemic iron levels. In the prior funding period, this grant supported our novel work demonstrating the central role of hemojuvelin (HJV) in the regulation of hepcidin. Our laboratory discovered that hemojuvelin is a BMP co-receptor whose BMP signaling ability is responsible for hepcidin regulation. Loss of HJV activity leads to the absence of hepcidin and iron overload (e.g. hemochromatosis), while excess BMP signaling leads to supraphysiologic levels of hepcidin and anemia. More recently, we have identified BMP6 as the key endogenous ligand for HJV. BMP6 binds directly to HJV protein and mice lacking BMP6 develop severe iron overload similar to HJV or hepcidin null mice. In addition, we have demonstrated that soluble HJV.Fc protein can effectively mobilize iron in mice by inhibition of endogenous BMP6 ligand. Thus, we have generated data that 1) HJV selectively binds BMP ligands, 2) HJV is required for hepcidin regulation, 3) HJV mutations in humans do not generate adequate BMP signals, 4) BMP6 is the endogenous ligand for HJV, 5) soluble HJV.Fc can mobilize iron in normal mice, and 6) the presence of HJV alters the ability of BMP ligands to utilize BMP type II receptors. In the next funding period, we propose to advance our investigations of the mechanisms of action of hemojuvelin by studying important unanswered questions regarding hemojuvelin biochemistry, cell biology, and in vivo physiology. Knowledge we gain from our studies may lead to new therapeutic strategies for the treatment of iron disorders.